Largescalesimulationsofmacromoleculesinsolutionthatdonot suffer from artifacts arising from force truncations are becoming feasible. New force evaluation algorithms such as the Fast Multipole Method (FMM) and multiple time scale integration methods such as the reversible Reference System Propogator Algorithm (r-RESPS) have been combined and used to perform fast and stable simulations of large macromolecular systems. A consistent treatment of the long-range forces in simulations with periodic boundary conditions requires the use of a periodic form of the Coulomb potential. In a previous publication we have discussed the origin and relevance from computer simulations of a strong finite-size effect which appears when using the Ewald summation formula and affects the electrostatic interaction energies. It can be understood as arising from a volume-dependent shift of the potential in a finite, periodic box relative to the infinite volume limit. This shift is due to the fact that the "zero of energy" for a periodic system cannot be defined by letting the interacting particles be separated by an infinite distance; the correct definition corresponds to setting its k = 0 Fourier mode to zero. Other groups have discussed related but different finite size effects in the context of the free energy of charging an ion. One of the goals of our studies is to determine to what extent do these finite-size effects affect the pKa calculations on a system as complex as a protein.